EP2514739B1 - Substituierte Beta-phenyl-alpha-hydroxypropansäure, Syntheseverfahren und Verwendung davon - Google Patents

Substituierte Beta-phenyl-alpha-hydroxypropansäure, Syntheseverfahren und Verwendung davon Download PDF

Info

Publication number
EP2514739B1
EP2514739B1 EP12002538.2A EP12002538A EP2514739B1 EP 2514739 B1 EP2514739 B1 EP 2514739B1 EP 12002538 A EP12002538 A EP 12002538A EP 2514739 B1 EP2514739 B1 EP 2514739B1
Authority
EP
European Patent Office
Prior art keywords
ester
acid
bornyl
group
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP12002538.2A
Other languages
English (en)
French (fr)
Other versions
EP2514739A1 (de
Inventor
Xiaohui Zheng
Qunzheng Zhang
Shixiang Wang
Xinfeng Zhao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Northwest University
North West University
Original Assignee
Northwest University
North West University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Northwest University, North West University filed Critical Northwest University
Priority to SI200731907A priority Critical patent/SI2514739T1/sl
Publication of EP2514739A1 publication Critical patent/EP2514739A1/de
Application granted granted Critical
Publication of EP2514739B1 publication Critical patent/EP2514739B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/48—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C07C69/653—Acrylic acid esters; Methacrylic acid esters; Haloacrylic acid esters; Halomethacrylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • Dan-shen Root Radix Salviae Militiorrhizae ) is a traditional Chinese medicine for treatment of cardiovascular and cerebrovascular diseases with definite therapeutic effects.
  • salvianic acid chemical name: ⁇ -(3,4-dihydroxyphenyl)- ⁇ -hydroxyl-propionic acid
  • ⁇ -phenyl- ⁇ -hydroxylpropionic acid is the pharmacologically active portion in propanoid acid, but its potency is not desirable.
  • the substituted ⁇ -phenyl- ⁇ -hydroxylpropionic acid was modified, and the resulting modified derivatives might possess the same or greater potency than the parent compound, and might also exhibit an improved therapeutic effect in the treatment and prevention of cardiovascular and cerebrovascular diseases.
  • borneol is capable of passing through cardiocerebral barrier, while propanoid acid is not prone to pass through cardiocerebral barrier. Therefore, propanoid acid may be modified in structure by incorporating the chemical structure of borneol.
  • One object of the present invention is to provide a substituted ⁇ -phenyl- ⁇ -hydroxy-propionic acid derivative and a process for synthesizing the same, as well as use of the substituted ⁇ -phenyl- ⁇ -hydroxy-propionic acid derivative in the manufacture of a medicament for prevention and treatment of cardiovascular and cerebrovascular diseases.
  • said process comprises: reacting a compound of the formula (V) with a compound of the formula (VI) or a hydrate thereof in the present of a catalyst:
  • the reaction molar ratio of the compound of the formula (V) to the compound of the formula (VI) can be 1:0.8 ⁇ 1:1.5, preferably 1:1 ⁇ 1:1.5, more preferably 1:1.25 ⁇ 1:1.5, most preferably 1:1.5.
  • the reaction temperature can be varied depending on the solvent being used. Advantageously, it is controlled within the range of 0°C ⁇ 150°C. Preferably, the reaction temperature is 25°C ⁇ 100°C. More preferably , the reaction temperature is 65°C.
  • the reaction duration can be 2h ⁇ 24h, preferably 5h ⁇ 15h, more preferably 8h ⁇ 12h, most preferably 8h.
  • the compound of the present invention for use in the prevention and treatment of cardiovascular or cerebrovascular diseases.
  • the catalyst S 2 O 8 2- /ZrO 2 was prepared by a process comprising the following steps: preparing a solution of 1mol ⁇ L -1 ZrOCl 2 with 0.025mol ZrOCl 2 ⁇ 8H 2 O; stirring in an ice-water bath; adding slowly 6 mol ⁇ L -1 aqueous ammonia dropwise until pH reached 10; aging for 12h.
  • the resulting solution was washed with saturated NaHCO 3 solution to remove unreacted ⁇ -(3,4-dihydroxylphenyl) - ⁇ -hydroxylpropionic acid and p-toluene sulfonic acid.
  • the obtained ethyl acetate layer was concentrated under reduced pressure, resulting in a brown viscous substance, which was further separated by column chromatography, obtaining a yellowish oil.
  • the resultant yellowish oil has the same mass spectrum and infrared spectrum as that in Example 1.
  • Example 2 The synthesis was performed through the same procedure of Example 1, except that 0.1 mol ⁇ -(3,4-dihydroxylphenyl)- ⁇ -hydroxylpropionic acid and 0.12mol borneol were added to the three-necked flask, then 1.33g S 2 O 8 2- /ZrO 2 as catalyst and 400mL 1,4-dioxane were added, and the reaction was performed at 100°C for 8h. After the completion of the reaction, the catalyst S 2 O 8 2- /ZrO 2 was removed by sucking filtration, and the solvent was removed by vacuum distillation, and the resulting viscous substance was treated by vacuum (1.3 ⁇ 10 -3 Pa) using an oil pump in a boiling-water bath to remove borneol. The resultant black brown viscous substance was separated using column chromatography, obtaining a yellowish oil, which has the same mass spectrum and infrared spectrum as that in Example 1.
  • Example 2 The synthesis was performed through the same procedure of Example 1, except that 0.06mol ⁇ -(3,4-dihydroxylphenyl)- ⁇ -hydroxylpropionic acid and 0.09mol borneol were added to the three-necked flask, then 0.60g aluminum trichloride as catalyst and 200mL N,N- dimethylformamide as solvent were added, and the reaction was performed at 150°C for 10h. After the completion of the reaction, the solvent was removed by vacuum distillation, and the resulting viscous substance was treated by vacuum (1.3 ⁇ 10 -3 Pa) using an oil pump in a boiling-water bath to remove borneol. The resultant black brown substance was separated using column chromatography, obtaining a yellowish oil, which has the same mass spectrum and infrared spectrum as that of Example 1.
  • Trachea cannula was inserted into the rats and they were allowed to spontaneous respire. Right common jugular vein and common carotid artery were isolated and a suture was introduced for later use. Animals were fixed on a rat stereotaxic apparatus, a cranial window with a size of 6x8mm was opened at the right temple with a dental drill, after hemostasis, cerebral dura mater was cut open with scissors to expose cerebral pia mater. The window was covered and sealed with glass and dental cement, and the laser probe of a laser-doppler microcirculatory blood flow meter was fixed on the cranial window.
  • the suture was further penetrated by about 1mm, and the distal end of the cut and the suture in the artery were ligated securely. Spare suture was cut-off. After the end of the test, it was checked whether the nylon suture blocked the initiation site of the middle cerebral artery, and the data of any animal whose artery was not blocked were cancelled. The animals of the control group were not treated. After the cranial window was prepared, the probe of J 12200 type laser-doppler microcirculatory blood flow meter was fixed at the cranial window, and the probe was maintained without displacement and rotation during the whole test.
  • microcirculatory blood flows before ligation and 5, 15, 30, 45 and 60min after ligation were recorded, and the data of the animals in the drug-treatment groups were recorded at the same time points.
  • the mean microcirculatory blood flow observed within 1min at each time point was designated as the microcirculatory blood flow of the respective time point. Table 1.
  • mice having a body weight of 220 ⁇ 20g were randomly divided into model control group, salvianic acid injection group (im 1mL/kg), and group of bornyl ⁇ -(3,4-dihydroxylphenyl)- ⁇ -hydroxylpropionate ester at a small, middle and large dose (ip 5, 15, 35mg/kg).
  • the rats of the normal group and the model control group were ip administered with equal-volume of physiologic saline.
  • the rats of all groups were administered for consecutive 5 days.
  • the slices were fixed with 10% formaldehyde for 24h to enhance staining color for contrast photography.
  • the myocardial tissue was divided into: normal myocardia in blue, ischemic myocardia in light red, and necrotic myocardia in gray.
  • Standard immunohistochemistry ABC and SP methods were employed for staining.
  • Bax anti-rabbit polyclonal antibody (Santa CruzBio. Inc.) at a dilution of 1:200; Bcl22: anti-rabbit polyclonal antibody (TBD Tianjin Biotechnological Center).
  • caspase-3 anti-rabbit polyclonal antibody (Normarkers Fromont, CA)
  • MMP-2 anti-murine monoclonal antibody (Normarkers Fromont, CA) at a dilution of 1:200;
  • PPAR ⁇ anti-caprine polyclonal antibody (Santa Cruz Bio.
  • Rats were anesthetized by intraperitoneal injection of 20% urethane 5mL/kg and fixed; the skin of neck of rats were incised, anterior cervical muscles were isolated, trachea was exposed, and tracheal cannula was inserted; common carotid artery was isolated, a cardiac catheter was introduced through the common carotid artery into left ventricle, the left intraventricular pressure was measured with a pressure transducer (T-200) of RM-6000 multi-channel polygraph and the carrier amplifier (AP-601G) of RM-6000 multi-channel polygraph, then the signals of the left intraventricular pressure were input to the differential amplifier (ED-601 G) of RM-6000 multi-channel polygraph to record the maximum rate of increasing and decreasing the left intraventricular pressure (dp/dt max -dp/dt max ); right femoral artery was isolated, the arterial blood pressure was measured by using cannula; a recording electrode of electrocardiograph was connected to record type II electrocardiogram. All data were input into
  • the abdomen was opened 1.5cm below xiphoid bone to isolate duodenum, a small incision was formed on the duodenum away from blood vessels by ophthalmic scissors, a catheter was inserted and the incision was fixed by suture for administration. After the end of operation and a further waiting period of 30min, normal data were recorded once the indexes to be monitored were stable.
  • Test drugs were duodenally administered via the catheter, and the indexes were monitored 5, 15, 30, 60, 90 and 120min after the administration.
  • the left intraventricular pressure of anesthetized rats significantly decreased after administration, and significant differences (P ⁇ 0.05 or P ⁇ 0.01) from the blank control group were observed at 15, 30, 60, 90 and 120 min; in the 9mg/kg group of bornyl salvianate ester, the left intraventricular pressure of anesthetized rats exhibited a decrease tendency, and significant differences (P ⁇ 0.05 or P ⁇ 0.01) from the blank control group were observed at 60 min; in the 4.5mg/kg group of bornyl salvianate ester, the left intraventricular pressure of anesthetized rats was not significantly affected after administration, and no significant difference from the blank control group was observed; while verapamil hydrochloride significantly reduced the left intraventricular pressure of anesthetized rats, and significant differences (P ⁇ 0.01) from the model control group were observed (Table 8).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Claims (12)

  1. Eine Verbindung mit der Formel (I):
    Figure imgb0037
    worin R1 und R2 unabhängig voneinander OH sind, und R3 ausgewählt ist aus der Gruppe bestehend aus H, OH, F, Cl, Br, Methoxy und Ethoxy; oder alternativ R1 und R2 zusammen -OCH2O- bilden, und R3 ausgewählt ist aus der Gruppe bestehend aus H, OH, Methoxy, Ethoxy und Halogenen;
    R4 OH, Acyloxy, Aroyloxy oder mit einem heterocyclischen Radikal substitutiertes Acyloxy ist;
    R5 ausgewählt ist aus Cycloalkoxyl,
    Figure imgb0038
     und
    Figure imgb0039
     vorausgesetzt, dass, wenn R1 und R2 OH sind, R3 H ist, und R4 OH ist, dann R5 nicht
    Figure imgb0040
     ist.
  2. Die Verbindung gemäß Anspruch 1, worin R4 OH ist.
  3. Die Verbindung gemäß Anspruch 1, worin R4 o-Acetoxybenzoyloxy, 3-Pyridinylbenzoyloxy oder 4-Pyridinylbenzoyloxy ist.
  4. Die Verbindung gemäß irgendeinem der Ansprüche 1-3, worin R5 ist:
    Figure imgb0041
     oder
    Figure imgb0042
  5. Die Verbindung gemäß Anspruch 1, worin R1 und R2 zusammen -OCH2O-bilden.
  6. Die Verbindung gemäß Anspruch 5, worin R3=H, R4=
    Figure imgb0043
     oder
    Figure imgb0044
  7. Die Verbindung gemäß Anspruch 5, worin R3=H, R4=
    Figure imgb0045
     R5=
    Figure imgb0046
  8. Die Verbindung gemäß Anspruch 5, worin R3=H, R4=OH, R5=
    Figure imgb0047
     oder
    Figure imgb0048
  9. Ein Verfahren zur Synthese einer Verbindung gemäß Anspruch 1, welches umfasst die Reaktion einer Verbindung der Formel (III) mit einer Verbindung der Formel (IV) oder einem Hydrat davon in der Gegenwart eines Katalysators:
    Figure imgb0049
     wobei R1, R2, R3, R4 und R5 dieselbe Bedeutung haben wie in der Formel (I), vorausgesetzt, dass, wenn R1 und R2 OH sind, R3 H ist, und R4 OH ist, dann R5 nicht
    Figure imgb0050
     ist; oder welches umfasst die Reaktion einer Verbindung der Formel (V) mit einer Verbindung der Formel (VI) oder einem Hydrat davon in der Gegenwart eines Katalysators:
    Figure imgb0051
     wobei R1, R2, R3 und R5 dieselbe Bedeutung haben wie in der Formel (I), und R4' Acyloxy ist;
    wobei der Katalysator konzentrierte H2SO4, Siliciumwolframsäure, Phosphomolybdänsäure, p-Toluolsulfonsäure, S 2 O 8 2 − / ZrO 2 ,
    Figure imgb0052
     Aluminiumtrichlorid, Zinkchlorid und/oder Magnesiumchlorid ist.
  10. Das Verfahren gemäß Anspruch 9, worin die Reaktion in einem Lösemittel durchgeführt wird.
  11. Das Verfahren gemäß Anspruch 10, wobei das Lösemittel Ethylacetat, Dichlormethan, Tetrahydrofuran, Aceton, Toluol, 1,4-Dioxan und N,N-Dimethylformamid, einzeln oder in irgendeiner Kombination, ist.
  12. Eine Verbindung gemäß irgendeinem der Ansprüche 1 bis 8 zur Verwendung in der Vorbeugung oder Behandlung von kardiovaskulären oder cerebrovaskulären Erkrankungen.
EP12002538.2A 2006-05-15 2007-05-14 Substituierte Beta-phenyl-alpha-hydroxypropansäure, Syntheseverfahren und Verwendung davon Active EP2514739B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI200731907A SI2514739T1 (sl) 2006-05-15 2007-05-14 Substituirana beta-fenil-alfa-hidroksi propanojska kislina, postopek sinteze in njena uporaba

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2006100427873A CN100415709C (zh) 2006-05-15 2006-05-15 β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途
EP07721123A EP2019090B1 (de) 2006-05-15 2007-05-14 Substituierte beta-phenyl-alpha-hydroxypropansäure, syntheseverfahren und anwendung davon

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP07721123A Division EP2019090B1 (de) 2006-05-15 2007-05-14 Substituierte beta-phenyl-alpha-hydroxypropansäure, syntheseverfahren und anwendung davon

Publications (2)

Publication Number Publication Date
EP2514739A1 EP2514739A1 (de) 2012-10-24
EP2514739B1 true EP2514739B1 (de) 2016-12-21

Family

ID=37442796

Family Applications (2)

Application Number Title Priority Date Filing Date
EP12002538.2A Active EP2514739B1 (de) 2006-05-15 2007-05-14 Substituierte Beta-phenyl-alpha-hydroxypropansäure, Syntheseverfahren und Verwendung davon
EP07721123A Active EP2019090B1 (de) 2006-05-15 2007-05-14 Substituierte beta-phenyl-alpha-hydroxypropansäure, syntheseverfahren und anwendung davon

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP07721123A Active EP2019090B1 (de) 2006-05-15 2007-05-14 Substituierte beta-phenyl-alpha-hydroxypropansäure, syntheseverfahren und anwendung davon

Country Status (20)

Country Link
US (1) US8017786B2 (de)
EP (2) EP2514739B1 (de)
JP (1) JP5094845B2 (de)
KR (1) KR101059639B1 (de)
CN (1) CN100415709C (de)
AU (1) AU2007250364B8 (de)
BR (1) BRPI0712101B8 (de)
CA (1) CA2652299C (de)
CY (2) CY1113676T1 (de)
DK (2) DK2019090T3 (de)
ES (1) ES2618677T3 (de)
HU (1) HUE032505T2 (de)
IL (1) IL195313A (de)
MY (1) MY148134A (de)
NZ (1) NZ572958A (de)
PL (2) PL2019090T3 (de)
PT (1) PT2514739T (de)
RU (1) RU2421443C2 (de)
SI (2) SI2514739T1 (de)
WO (1) WO2007131446A1 (de)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100415709C (zh) 2006-05-15 2008-09-03 西北大学 β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途
CN101607897B (zh) * 2008-06-18 2012-10-24 复旦大学 (z)-2-乙酰氧基-3-(3,4-二羟基苯基)丙烯酸及其合成方法和用途
WO2011130194A2 (en) 2010-04-12 2011-10-20 Supernus Pharmaceuticals Inc. Methods for producing viloxazine salts and novel polymorphs thereof
CN102030648B (zh) * 2010-12-07 2013-04-03 西北大学 3-(3,4-二羟基苯基)-2-羟基丙酸酯的不对称合成方法
CN102432468B (zh) * 2011-11-21 2014-03-26 中国人民解放军第四军医大学 丹参素冰片酯的不对称合成方法
WO2014091465A2 (en) * 2012-12-16 2014-06-19 Mahesh Kandula Compositions and methods for the treatment of metabolic syndrome and lipid disorders
CN103232347B (zh) * 2013-04-12 2015-09-16 合肥工业大学 一种cns药物的脑靶向前药及其制备方法以及冰片在cns药物脑靶向前药中的用途
CN103570546B (zh) * 2013-10-09 2016-05-18 西安石油大学 一种丹参素冰片酯的工业化合成方法
CN103570547B (zh) * 2013-10-09 2016-04-20 西安石油大学 一种丹参素异丙酯的工业化合成方法
CN105693817B (zh) 2014-11-27 2020-06-05 西北大学 一类三肽化合物及其制备方法与应用
CN106496897A (zh) * 2016-10-14 2017-03-15 无锡三帝特种高分子材料有限公司 一种聚酯镀铝膜
CN107619376A (zh) * 2017-11-09 2018-01-23 宁波职业技术学院 一种缬氨酸冰片酯及其制备方法和应用
CN109928959B (zh) * 2017-12-18 2020-11-06 中国科学院上海营养与健康研究所 抗心肌肥厚的药物、制备方法和用途
CN108047048B (zh) * 2017-12-30 2021-01-12 苏州沪云肿瘤研究中心股份有限公司 一种苯丙酸酯类化合物及其制备方法和应用
CN109608356B (zh) * 2018-12-14 2021-11-05 南京医科大学 一类丙二酸单酯酰化的氨基酸(+)2-崁醇酯的衍生物及其应用
JP6768868B2 (ja) * 2019-03-29 2020-10-14 健裕生技股▲分▼有限公司 心筋再生を促進させるための化合物、その調製方法及びこれらの使用
JP2020164528A (ja) * 2020-04-28 2020-10-08 健裕生技股▲分▼有限公司 心筋再生を促進させるための化合物、その調製方法、医薬組成物及びこれらの使用
CN114394901A (zh) * 2021-12-30 2022-04-26 广东医科大学附属第二医院 一种丹参素特戊酸甲酯衍生物及其制备方法
US11891353B1 (en) 2023-08-28 2024-02-06 King Faisal University 3,3′-(hydrazine-1,2-diyl)bis(1-(naphthalen-2-yloxy)propan-2-ol) as an ecofriendly insecticidal agent against Spodoptera littoralis (boisd.)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1583710A (zh) * 2004-06-03 2005-02-23 西安交通大学 β－（3，4－二羟基苯基）－α－羟基丙酸异丙酯及其合成方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60255774A (ja) * 1984-06-01 1985-12-17 Dai Ichi Seiyaku Co Ltd テトラヒドロナフタレン誘導体
RU2092169C1 (ru) 1992-08-20 1997-10-10 Раиса Павловна Свистунова Местное противовоспалительное средство "сальвинол"
JP3050733B2 (ja) * 1992-10-16 2000-06-12 中外製薬株式会社 ４−アルコキシ−２，６−ジ−ｔ−ブチルフェノール誘導体
US5736537A (en) * 1995-09-12 1998-04-07 Estee Lauder, Inc. Dehydroep:androsterone sailcylate useful against skin atrophy
WO1997015546A1 (fr) * 1995-10-26 1997-05-01 Nippon Shinyaku Co., Ltd. Derives d'acide carboxylique et compositions pharmaceutiques
CN1161140C (zh) * 2001-11-09 2004-08-11 天津天士力制药股份有限公司 一种预防和治疗冠心病心绞痛的药物及其制备方法和其它用途
US20040248849A1 (en) * 2001-06-28 2004-12-09 Potlapally Rajender Kumar 3-Aryl-A-oxy substituted propanoic acids and a process for their preparation
FR2842523A1 (fr) * 2002-07-17 2004-01-23 Sanofi Synthelabo Derives d'acylaminothiazole, leur preparation et leur application en therapeutique
CN100415709C (zh) 2006-05-15 2008-09-03 西北大学 β-(3,4-二羟基苯基)-α-羟基丙酸冰片酯、其合成方法和用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1583710A (zh) * 2004-06-03 2005-02-23 西安交通大学 β－（3，4－二羟基苯基）－α－羟基丙酸异丙酯及其合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WREN H ET AL: "Studies in the resolution of racemic acids by optically active alcohols. Part II. The resolution of atrolactinic and alpha-hydroxy-beta-phenylpropionic acids by l-menthol", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL SOCIETY, LETCHWORTH; GB, vol. 119, 1 January 1921 (1921-01-01), pages 798 - 803, XP009183055, ISSN: 0368-1769 *

Also Published As

Publication number Publication date
CA2652299C (en) 2011-12-20
SI2514739T1 (sl) 2017-04-26
US8017786B2 (en) 2011-09-13
EP2019090A4 (de) 2010-01-27
HUE032505T2 (en) 2017-09-28
EP2514739A1 (de) 2012-10-24
BRPI0712101B8 (pt) 2021-05-25
BRPI0712101B1 (pt) 2020-08-11
PL2019090T3 (pl) 2013-02-28
EP2019090A1 (de) 2009-01-28
DK2019090T3 (da) 2013-01-21
US20090131677A1 (en) 2009-05-21
KR101059639B1 (ko) 2011-08-25
DK2514739T3 (en) 2017-04-03
JP2009537462A (ja) 2009-10-29
AU2007250364A1 (en) 2007-11-22
SI2019090T1 (sl) 2013-02-28
KR20090013231A (ko) 2009-02-04
RU2421443C2 (ru) 2011-06-20
CN1868998A (zh) 2006-11-29
BRPI0712101A2 (pt) 2012-01-17
ES2618677T3 (es) 2017-06-21
PT2514739T (pt) 2017-03-09
AU2007250364B2 (en) 2011-05-26
CY1118722T1 (el) 2017-07-12
IL195313A0 (en) 2009-08-03
IL195313A (en) 2013-12-31
CA2652299A1 (en) 2007-11-22
NZ572958A (en) 2011-11-25
RU2008145090A (ru) 2010-06-20
WO2007131446A1 (fr) 2007-11-22
MY148134A (en) 2013-02-28
AU2007250364B8 (en) 2012-01-19
CY1113676T1 (el) 2016-06-22
EP2019090B1 (de) 2012-11-14
PL2514739T3 (pl) 2017-09-29
CN100415709C (zh) 2008-09-03
JP5094845B2 (ja) 2012-12-12

Similar Documents

Publication Publication Date Title
EP2514739B1 (de) Substituierte Beta-phenyl-alpha-hydroxypropansäure, Syntheseverfahren und Verwendung davon
CA2502975A1 (en) Chromones and chromone derivatives and uses thereof
JP2672101B2 (ja) キサンテノン−４−酢酸誘導体
JP2009046486A (ja) ケルセチンのアナログまたは誘導体（プロドラッグ）
EP3419959A1 (de) Kombinationstherapie
CN103687843B (zh) 醌基一氧化氮供体化合物
FI90545C (fi) Menetelmä terapeuttisesti aktiivisten 2,2-dimetyylikromeenijohdannaisten valmistamiseksi
EP2767533B1 (de) Butylphthalidderivat, herstellungsverfahren dafür und verwendung davon
US7432306B2 (en) Method for preparing novel transcription factors and use
JP2008506722A (ja) シス−１，２−置換スチルベン誘導体、および糖尿病の治療および／または予防のための薬剤の製造におけるそれらの使用
RU2105554C1 (ru) N-(2,4,6-триметилфенилкарбамоилметил)-n-аллилморфолиний бромид, проявляющий противоишемическое и антиаритмическое действие при ишемической болезни сердца и способ его получения
JPH04368359A (ja) カプサイシン誘導体又はその酸エステルを有効成分とする鎮痛剤、血管拡張剤
CN114213381B (zh) 4-色满酮衍生物及其制备方法和医药用途
KR100516647B1 (ko) 당뇨병 치료제 조성물
EP0357092B1 (de) Herstellung von Diacetoxybenzylidendiacetaten
CA2518328C (en) Method for preparing transcription factors and use
CN118126100A (zh) 一种环烯醚萜苷化合物及其制备方法和应用
JP2005041828A (ja) 新規セラミド誘導体とその制がん剤などへの利用
JPH03246223A (ja) 抗高脂血症剤および抗動脈硬化症剤

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120410

AC Divisional application: reference to earlier application

Ref document number: 2019090

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1177929

Country of ref document: HK

17Q First examination report despatched

Effective date: 20140818

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 602007049277

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: C07C0069732000

Ipc: C07C0235340000

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 213/79 20060101ALI20160803BHEP

Ipc: C07C 235/34 20060101AFI20160803BHEP

Ipc: C07D 405/12 20060101ALI20160803BHEP

Ipc: C07D 317/60 20060101ALI20160803BHEP

Ipc: C07C 69/732 20060101ALI20160803BHEP

Ipc: C07D 213/80 20060101ALI20160803BHEP

INTG Intention to grant announced

Effective date: 20160822

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AC Divisional application: reference to earlier application

Ref document number: 2019090

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 855329

Country of ref document: AT

Kind code of ref document: T

Effective date: 20170115

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602007049277

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20161221

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Ref document number: 2514739

Country of ref document: PT

Date of ref document: 20170309

Kind code of ref document: T

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20170301

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20170327

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20161221

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2618677

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20170621

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20161221

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170321

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 23708

Country of ref document: SK

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602007049277

Country of ref document: DE

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E032505

Country of ref document: HU

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20170922

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20161221

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1177929

Country of ref document: HK

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170514

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 855329

Country of ref document: AT

Kind code of ref document: T

Effective date: 20161221

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20230511

Year of fee payment: 17

Ref country code: CH

Payment date: 20230602

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SK

Payment date: 20230418

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20240524

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20240524

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IS

Payment date: 20240516

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20240517

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20240626

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240613

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20240527

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20240517

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20240617

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CZ

Payment date: 20240515

Year of fee payment: 18

Ref country code: AT

Payment date: 20240521

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: RO

Payment date: 20240523

Year of fee payment: 18

Ref country code: IT

Payment date: 20240515

Year of fee payment: 18

Ref country code: FR

Payment date: 20240531

Year of fee payment: 18

Ref country code: FI

Payment date: 20240521

Year of fee payment: 18

Ref country code: SI

Payment date: 20240514

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20240514

Year of fee payment: 18

Ref country code: PT

Payment date: 20240514

Year of fee payment: 18

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20240514

Year of fee payment: 18

Ref country code: SE

Payment date: 20240516

Year of fee payment: 18

Ref country code: HU

Payment date: 20240605

Year of fee payment: 18

Ref country code: BE

Payment date: 20240528

Year of fee payment: 18